Traumatic CNS injury causes several neurological disorders that are characterized by a delayed increase in excitability, such as posttraumatic epilepsy, by unknown mechanisms. In this proposal, we focus on two fundamental pre- and postsynaptic consequences of traumatic injury that may account for hyperexcitability in these conditions: axonal injury and denervation of neuronal populations. The Hypotheses: Neuronal excitability is increased after a penetrating injury because 1) the release of neurotrophins triggers presynaptic axonal sprouting, and 2) degeneration of severed axons triggers an increase in the intrinsic postsynaptic excitability of partially denervated cells. If so, then preventing axonal sprouting and restoring postsynaptic excitability will alleviate injury- induced hyperexcitability and provide useful therapeutic approaches for posttraumatic epilepsy. The Model: We will test these hypotheses in a model of penetrating CNS injury in rats and genetically altered mice. Posttraumatic epilepsy will be studied electrophysiologically and morphologically in ex vivo hippocampal slices and in hippocampal slice cultures at various times after making a transection of the Schaffer collateral pathway because axonal injury and neuronal denervation can be spatially confined to the CA3 and CA1 regions, respectively. AIM 1: Determine the role of presynaptic axonal sprouting as a cause of injury-induced hyperexcitability in the hippocampus in vitro and in vivo. Mice in which the trkB neurotrophin receptor has been modified to render it sensitive to pharmacological blockade will be used to test the hypothesis that activation of trkB receptors is required for axonal sprouting and hyperexcitability. AIM 2: Determine the postsynaptic mechanisms underlying injury-induced hyperexcitability in the hippocampus. We will test the hypotheses that glutamate supersensitivity and increased intrinsic hyperexcitability occur in CA1 pyramidal cells after denervation. The Goal: To better understand the causes of posttraumatic epilepsy and, ultimately, to offer new and improved prophylactic therapeutic strategies to cure or prevent these conditions. Project Narrative: We seek to discover the causes of the form of epilepsy that occurs after a severe head injury and to develop new therapies to treat or prevent this condition.